The influence of liver transplantation on the pharmacokinetics of the immunosuppressive agent cyclosporin A will be studied in dogs and the data obtained from these studies will be employed in the determination of a maximum safe concentration and a minimum effective concentration of cyclosporin A in the serum. Initially, time course studies in normal dogs (no surgery) following a series of single rapid intravenous doses, will identify any nonlinear disposition kinetics which might be encountered throughout this proposed project. Then following liver transplantation or shamtransplantation, a selected dose of CyA will be administered by rapid intravenous injection and the time course will be studied in serum and urine. These studies will also be conducted using control dogs (no surgery). Cyclosporin A concentrations will be determined by liquid chromatography and all standard pharmacokinetic parameters will be determined by digital computer. Statistical analysis will evaluate any observed differences between parameters from test and control animals. Further studies will be carried out following oral administration of the same dose. Absolute bioavailability (to include rate and extent of administered dose which appears in the serum) will be determined using standard calculation techniques. Further work will employ obtained data and additional studies in attempts to relate cyclosporin A pharmacokinetics to therapeutic and toxic effects and define a maximum safe concentration and a minimum effective concentration of of cyclosporin A in serum. Findings from these proposed studies should support and simplify future work which will employ pharmacokinetic data in the optimization of cyclosporin A therapy in human liver transplantation.